Fused-ring heterocycles for the treatment of atherosclerosis

ABSTRACT

This invention relates to pyrazolo pyrimidines for the treatment of atherosclerosis as inhibitors of acyl--CoA, cholesterol acyetransferase (ACAT), and their use as antihypercholesterolemic agents, pharmaceutical compositions and preparation, and having the formula (I): ##STR1## wherein: A and Q are selected independently from CH or N with no more than two nitrogens per ring: 
     D, E, and G are selected independently from CR 1  or N with no more than two nitrogens per ring; 
     X is S(O) r , O, NR 4  or CH 2  ; 
     J is C 2  -C 10  alkyl, C 3  -C 10  branched alkyl, C 3  -C 10  alkenyl or C 3  -C 10  alkynyl; 
     Y is O, S, H 2  or NH: 
     Z is NHR 3 , OR 3  or R 3  : 
     R 1  is selected independently from H, NO 2 , Br, Cl, F, CF 3 , CN, CH 3  S(O) r , C 1  -C 8  alkyl or alloxy, C 3  -C 8 , branched alkyl, C 1  -C 4  carboalkoxy, NR 5  R 6  or NR 5  COR 6  ; 
     R 2  is C 1  -C 8  alkyl, C 3  -C 8  branched alkyl, C 3  -C 7  cycloalkyl, C 3  -C 8  alkenyl or alkynyl, C 7  -C 14  araalkyl where the aryl group is optionally substituted; phenyl optionally substituted benzyl optionally substituted 2-, 3-, or 4- pyridinyl, pyrimidinyl: or biphenyl: 
     R 3  is C 1  -C 8  alkyl, C 3  -C 8  branched alkyl, C 3  -C 7  cycloalkyl, C 4  -C 10  cycloallylalkyl, C 3  -C 6  alkenyl or alkynyl, C 1  -C 3  perfluoroalkyl, C 7  -C 14  araalkyl where the aryl group is optionally substituted phenyl optionally substituted benzyl optionally substituted 2-, 3-, or 4- pyridinyl, pyrimidinyl; or biphenyl: 
     R 4  is H, C 1  -C 6  alkyl or benzyl; 
     R 5  and R 6  are selected independently from H or C 1  -C 4  alkyl; 
     r is 0 to 2: 
     or a pharmaceutically acceptable salt thereof.

FIELD OF THE INVENTION

This invention relates to imidazoles as inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT), pharmaceutical compositionscontaining them, processes for their preparation, and their use asantihypercholesterolemic and/or antiatherosclerotic agents.

BACKGROUND OF THE INVENTION

Hypercholesterolemia is an established risk factor in the development ofatherosclerosis. Therapeutic agents which control the level of serumcholesterol have proven to be effective in the treatment of coronaryartery disease. While agents exist that can modulate circulating levelsof cholesterol carrying lipoproteins, these agents have little or noeffect on the intestinal absorption of cholesterol. Dietary cholesterolcan increase the level of serum cholesterol to levels which place anindividual at increased risk for the development or exacerbation ofatherosclerosis. Since much of the free or unesterified cholesterol thatis absorbed by intestinal mucosal cells must first be esterified by ACATprior to its incorporation and secretion into the bloodstream in largelipoprotein particles called chylomicrons, inhibition of ACAT can reducethe absorption of dietary cholesterol. In addition, the accumulation andstorage of cholesteryl esters in the arterial wall is associated withincreased activity of ACAT. Inhibition of the enzyme is expected toinhibit the formation or progression of atherosclerotic lesions inmammals.

There is an increasing number of patents in the literature disclosingcompounds which are useful as ACAT inhibitors in particular andantiatherosclerotic agents in general. For example, U.S. Pat. No. No.4,623,662, issued to De Vries on Nov. 18, 1986, discloses ureas andthioureas as ACAT inhibitors useful for reducing the cholesterol estercontent of an arterial wall, inhibiting atherosclerotic lesiondevelopment, and/or treatment of mammalian hyperlipidemia. U.S. Pat. No.4,722,927, issued to Holmes on Feb. 2, 1988, discloses disubstitutedpyrimidineamides of oleic and linoleic acids as ACAT inhibitors usefulfor inhibiting intestinal absorption of cholesterol.

U.S. Pat. No. 4,868,210, issued to Trivedi on Sep. 19, 1989, as well asU.S. Pat. No. 4,923,896, May 8, 1990, disclose certain N-2,6-dialkyl- orN-2,6-dialkoxyphenyl-N'-arylalkyl ureas as potent inhibitors of ACAT.

European Patent Application 354,994, filed by Meguro and Ikeda whichpublished on Feb. 21,1990, discloses certain N-aryl-N'-quinolin-4-ylureas as ACAT inhibitors. European Patent Application 370,740, filed byJackson et al. which published on May 30, 1990, discloses ACATinhibitors similar in composition to those of deVries (vide supra) butdifferent in constitution.

Billheimer, et al., European Patent Application EP-A-372,445, publishedon Jun. 13, 1990, discloses compounds of the formula: ##STR2## whereinR¹ and R² are selected independently from H, C₁ -C₈ alkyl, C₃ -C₈branched alkyl, C₃ -C₇ cycloalkyl, C₄ -C₁₀ cycloalkylalkyl, C₇ -C₁₄araalkyl, 2-, 3- or 4pyridinyl, 2-thienyl, 2-furanyl, phenyl optionallysubstituted with 1 to 3 groups selected from F, Cl, Br, OH, C₁ -C₄alkoxy, C₁ -C₄ alkyl, C₃ -C₈ branched alkyl, CH₃ S(O)_(r), NO₂, CF₃, orNR⁷ R⁸ ; or

R¹ and R² can also be taken together as ##STR3## where L is O,O(CH₂)_(m+1) O, or (CH₂)_(m) where m is 0-4; R³ is H, C₁ -C₆ alkyl,allyl, benzyl, or phenyl optionally substituted with F, Cl, CH₃, CH₃ O,or CF₃ ;

R⁴ is straight chain C₁ -C₈ alkyl optionally substituted with F; C₃ -C₈branched alkyl, C₃ -C₇ cycloalkyl, C₄ C₁₀ cycloalkylalkyl, C₇ -C₁₄araalkyl where the aryl group is optionally substituted with 1 to 3groups selected from C₁ -C₄ alkyl or alkoxy, F, Br, Cl, NH₂, OH, CN, CO₂H, CF₃, NO₂, C₁ -C₄ carboalkoxy, NR⁷ R⁸, or NCOR^(7;) C₃ -C₆ alkenyl oralkynyl, C₁ -C₃ perfluoroalkyl, phenyl optionally substituted with 1 to3 groups selected from C₁ -C₄ alkyl, C₃ -C₈ branched alkyl, C₁ -C₄alkoxy, F, Br, Cl, NH₂, OH, CN, CO₂ H, CF₃, NO₂, C₁ -C₄ carboalkoxy, NR⁷R⁸ or NCOR⁷ ; pentafluorophenyl, benzyl optionally substituted with 1 to3 groups selected from C₁ -C₄ alkyl or alkoxy, F, Br, Cl, NH₂, OH, CN,CO₂ H, CF₃, NO₂, C₁ -C₄ carboalkoxy, NR⁷ R⁸ or NCOR⁷ ; 2-, 3- or 4-pyridinyl, pyrimidinyl, or biphenyl;

R⁵ is H, C₁ -C₆ alkyl, or benzyl;

R⁶ is C₁ -C₈ alkyl, C₃ -C₈ branched alkyl, C₃ -C₇ cycloalkyl, C₃ -C₈alkenyl or alkynyl, phenyl optionally substituted with 1 to 3 groupsselected from C₁ -C₄ alkyl or alkoxy, F, Br, Cl, NH₂, OH, CN, CO₂ H,CF₃, NO₂, C₁ -C₄ carboalkoxy, NR⁷ R⁸, or NCOR⁷ ; pentafluorophenyl,benzyl optionally substituted with 1 to 3 groups selected from C₁ -C₄alkyl or alkoxy, F, Br, Cl, NH₂, OH, CN, CO₂ H, CF₃, NO₂, C₁ -C₄carboalkoxy, NR⁷ R⁸, or NCOR⁷ ;

R⁷ and R⁸ are selected independently from H or C₁ -C₄ alkyl;

X is S(O)_(r), O, NR⁵, CH₂ ;

A is C₂ -C₁₀ alkyl, C₃ -C₁₀ branched alkyl, C₃ -C₁₀ alkenyl, or C₃ -C₁₀alkynyl;

Y is O, S, H₂, NH;

Z is NHR⁴ , OR⁴ , or R⁴ ;

r is 0-2,

or a pharmaceutically acceptable salt thereof.

These compounds are potent in vitro inhibitors of ACAT and are thereforepotential antihypercholesterolemic agents.

U.S. Pat. No. 4,900,744, issued to Billheimer et al. on Feb. 13, 1990,discloses antihypercholesterolemic thioimidazoles of the formula:##STR4## or a pharmaceutically acceptable salt thereof, wherein R¹ andR² independently are H, F, Cl, CF₃, alkyl of 1 to 4 carbon atoms, oralkoxy of 1 to 4 carbon atoms;

A is alkylene of 7-20 carbon atoms of an alkenyl residue thereof with nomore than 2 double bonds;

R³ is H, CH₃, of C₂ H₅ ; and

n is 0, 1 or 2, such as 8-(4,5-diphenyl-1H-imidazol-2-ylthio)octanoicacid ethyl ester.

U.S. Pat. No, 4,460,598, issued to Lautenschlager et al. on Jul. 17,1984, discloses compounds of the formula: ##STR5## wherein R¹, R², R³,R⁴, R⁵ and R⁶ independently are H, F, Cl, Br, I, alkyl, alkoxy, or CF³,with the proviso that one or several of R¹ and R², R³ and R⁴ or R⁵ andR⁶ taken together represent methylenedioxy;

R⁷ is H, alkali metal ion, alkyl of 1 to 6 carbon atoms, or benzyl; and

n is 0 to 10.

The synthesis and the use of these compounds in the treatment ofthromboembolic, inflammatory and/or atherosclerotic diseases isdisclosed.

U.S. Pat. No. 4,654,358, issued to Lautenschlager et al. on Mar. 31,1987, discloses compounds of the formula: ##STR6## wherein k is 0, 1, or2,

R¹, R² and R³ independently are H, F, Cl, CH₃, CH₃ O, or CF₃ ;

R⁴ is H, Na, K, CH₃, CH₃ CH₂, (CH₃)₂ CH, CH₃ (CH₂)₂, or butyl;

A is C(CH₃)₂, CH(CH₂)_(m) CH₃, (CH₂)_(n), or (CH₂)_(n-2) CH(CH₃);

m is 0 to 8; and

n is 2 to 10.

The synthesis and the use of these compounds in the treatment ofinflammatory diseases, diseases of lipid metabolism, and/orhyperlipidemic diseases is disclosed.

German Laid Open Application No. DE 3504679, Lautenschlager et al.,published Aug. 14, 1986, discloses compounds of the formula: ##STR7##wherein R¹, R² and R³ independently are H, alkyl of 1 to 6 carbon atoms,cycloalkyl of 1 to 6 carbon atoms, or ##STR8## R⁴ and R⁵ independentlyare H, C₆ H₅, or alkyl of 1 to 9 carbon atoms;

R⁶ and R⁷ independently are H, OH, saturated or unsaturated alkyl,cycloalkyl, or hydroxyalkyl of 1 to 10 carbon atoms, ##STR9## R⁸, R⁹,R¹⁰, R¹¹, R¹² and R¹³ independently are H, F, Cl, BE, NO₂, CH₃ CONH, OR,alkyl of 1 to 3 carbon atoms, CF₃, and alkoxy of 1 to 3 carbon atoms,with the proviso that R⁸ and R⁹, R¹⁰ and R¹¹, or R¹² and R¹³ takentogether represent methylenedioxy;

R¹⁴ is alkyl of 1 to 2 carbon atoms;

m and n taken together represent a whole number from 0 to 9;

p is 0 to 2;

s is 0 to 2; and

t is 0 or 2.

The synthesis and the use of these compounds in the treatment ofthromboembolic, inflammatory, atherosclerotic, and lipid metabolismdiseases in general is disclosed.

German Laid Open Application No. DE 3504680, Lautenschlager et al.,published Aug. 14, 1986, discloses compounds of the formula: ##STR10##wherein R¹, R² and R³ independently are H, alkyl of 1 to 6 carbon atoms,cycloalkyl of 1 to 6 carbon atoms, or ##STR11## R¹ and R² can be takentogether with the carbon atoms in the 4 and 5 position of the imidazolering to represent a carbocyclic five- or six-membered aromatic orpartially hydrogenated ring which may be substituted by R⁸ or R⁹ ;

R⁴ and R⁵ independently are H, C₆ H₅, or alkyl of 1 to 9 carbon atoms;

R⁶ is alkyl, cycloalkyl, or hydroxyalkyl of 1 to 20 carbon atoms, H,alkali metal if X is --COO--, 1-phenethyl, or ##STR12## R⁷ is H, OH if Xis --CONR⁷ -- or alkyl of 1 to 4 carbon atoms; R⁸, R⁹, R¹⁰ and R¹¹ areindependently H, Cl, F, Br, NO₂, CH₃ CONH, OH, alkyl of 1 to 3 carbonatoms, CF₃, or alkoxy of 1 to 3 carbons, or R⁸ and R⁹ or R¹⁰ and R¹¹taken together represent methylenedioxy;

X is a bond, O, OC (═O)O, C(═O) O, CONR⁷ OC (═O), or OC(═O) NR⁷ ;

m and n taken together represent a whole number from 0 to 9;

p is 0 to 2;

s is 0 to 2; and

t is 0 or 2.

The synthesis and the use of these compounds in the treatment ofthromboembolic, inflammatory, atherosclerotic, and lipid metabolismdiseases in general is disclosed.

Durant et al., U.S. Pat. No. 4,228,291, issued Oct. 14, 1980, teachescompounds of the formula: ##STR13## wherein A together with the carbonatom form an unsaturated heterocyclic nucleus which may be an imidazole,pyrazole, pyrimidine, pyrazine, pyridazine, thiazole, isothiazole,oxazole, isoxazole, triazole, thiadiazole, benzimidazole, or 5, 6,7,8-tetrahydroimidazol[1, 5-a]pyridine ring;

X₁ is H, lower alkyl, hydroxyl, trifluoromethyl, benzyl, halogen, amino,or ##STR14## X₂ is H, or when X₁ is lower alkyl, lower alkyl or halogen;k is 0 to 2;

m is 2 or 3, provided that the sum of k and m is 3 or 4;

Y is O, S, or NH;

E i s NR₂ ;

R₁ is H, lower alkyl or di-lower alkyl amino-lower alkyl; and

R₂ is H, nitro, or cyano.

The compounds are said to be antihistamines of the H₂ receptor blockingtype, as well as having anti-inflammatory activity.

White, U.S. Pat. No. 4,413,130, Nov. 1, 1983, discloses histamine H₂receptor antagonists of the formula: ##STR15## wherein A together withthe carbon atom form an unsaturated heterocyclic nucleus which may be animidazole, pyridine, thiazole, isothiazole, oxazole, isoxazole,pyrazole, triazole, thiadiazole, pyrimidine, pyrazine or pyridazine;

X₁ and X₂ may be H, lower alkyl, trifluoromethyl, hydroxyl, halogen,amino, or X₁ and X₂ and at least two of the atoms comprising A may forma further ring;

k is 0 to 2;

m is 2 or 3, provided that the sum of k and m is 3 or 4;

E is O, S, or NR₂ ;

R₁ is H, lower alkyl, acyl, or dialkylaminoalkyl; and

R₂ is H, NO₂, CN, alkanesulfonyl or arenesulfonyl.

There are no known literature references disclosing the compounds ofthis invention, their use as ACAT inhibitors, or their use to lowercholesterol or in the treatment of atherosclerosis.

The compounds of this invention are very potent ACAT inhibitors and thusare expected to be useful in pharmaceutical formulations for thetreatment of atherosclerosis. This invention should not be construed aslimited to any particular antihypercholesterolemic mechanism of action.

SUMMARY OF THE INVENTION

The present invention provides novel compounds of Formula (I), processesfor their preparation, pharmaceutical compositions cantaining suchfused-ring heterocycles, and therapeutic methods for their use asantihypercholesterolemic agents.

This invention provides compounds of Formula (I): ##STR16## wherein: Aand Q are selected independently from CH or N with no more than twonitrogens per ring;

D, E, and G are selected independently from CR¹ or N with no more thantwo nitrogens per ring;

X is S (O)_(r), O, NR⁴ or CH₂ ;

J is C₂ -C₁₀ alkyl, C₃ -C₁₀ branched alkyl, C₃ -C₁₀ alkenyl or C₃ -C₁₀alkynyl;

Y is O, S, H₂ or NH;

Z is NHR³ OR³ or R³ ;

R¹ is selected independently from H, Br, Cl, F, CF₃, CN, NO₂, CH₃S(O)_(r), C₁ -C₈ alkyl or alkoxy, C₃ -C₈ branched alkyl, C₁ -C₄carboalkoxy, NR⁵ R⁶ or NR⁵ COR⁶ ;

R² is C₁ -C₈ alkyl, C₃ -C₈ branched alkyl, C₃ -C₇ cycloalkyl, C₃ -C₈alkenyl or alkynyl, C₇ -C₁₄ araalkyl where the aryl group is optionallysubstituted with 1 to 3 groups selected from C₁ -C₄ alkyl or alkoxy, F,Br, Cl, OH, CN, CO₂ H, CF₃, C₁ -C₄ carboalkoxy, NR⁵ R⁶, or NR⁵ COR⁶ ;phenyl optionally substituted with 1 to 3 groups selected from C₁ -C₄alkyl or alkoxy, F, Br, Cl, OH, CN, CO₂ H, CF₃, C₁ -C₄ carboalkoxy, NR⁵R⁶ or NR⁵ COR⁶ ; benzyl optionally substituted with 1 to 3 groupsselected from C₁ -C₄ alkyl or alkoxy, F, Br, Cl, OH, CN, CO₂ H, CF₃, C₁-C₄ carboalkoxy, NR⁵ R⁶, or NR.sup. 5 COR⁶ ; 2-, 3-, or 4- pyridinyl,pyrimidinyl; or biphenyl;

R³ is C₁ -C₈ alkyl, C₃ -C₈ branched alkyl, C₃ -C₇ cycloalkyl, C₄ -C₁₀cycloalkylalkyl, C₃ -C₆ alkenyl or alkynyl, C₁ -C₃ perfluoroalkyl, C₇-C₁₄ araalkyl where the aryl group is optionally substituted with 1 to 3groups selected from C₁ -C₄ alkyl or alkoxy, F, Br, Cl, OH, CN, CO₂ H,CF₃, C₁ -C₄ carboalkoxy, NR⁵ R⁶, or NR⁵ COR⁶ ; phenyl optionallysubstituted with 1 to 3 groups selected from C₁ -C₄ alkyl or alkoxy, C₃-C₈ branched alkyl, F, Br, Cl, OH, CN, CO₂ H, CF₃, C₁ -C₄ carboalkoxy,NR⁵ R⁶ or NR⁵ COR⁶ ; benzyl optionally substituted with 1 to 3 groupsselected from C₁ -C₄ alkyl or alkoxy, F, Br, Cl, OH, CN, CO.sub. 2 H,CF₃, C₁ -C₄ carboalkoxy, NR⁵ R⁶ or NR⁵ COR⁶ ; 2-, 3-, or 4-pyridinyl,pyrimidinyl; or biphenyl;

R⁴ is H, C₁ -C₆ alkyl or benzyl;

R⁵ and R⁶ are selected independently from H or C₁ -C₄ alkyl;

r is 0to 2;

or a pharmaceutically acceptable salt thereof.

More preferred are compounds of Formula (I) wherein:

X is S(O)_(r) ;

J is C₂ -C₁₀ alkyl or C₄ -C₉ branched alkyl;

Y is O;

Z is NHR³ ;

R¹ is selected independently from H, NO₂, C₁ -C₈ alkyl or alkoxy, C₃ -C₈branched alkyl, C₁ -C₄ carboalkoxy, NR⁵ R⁶ or NR⁵ COR⁶ ;

R² is C₁ -C₈ alkyl, C₃ -C₈ branched alkyl, C₃ -C₇ cycloalkyl, C₇ -C₁₄araalkyl where the aryl group is optionally substituted with 1 to 3groups selected from CH₃, CH₃ O, F, Br, Cl, OH, CN, CO₂ H, CF₃, NH₂,NO₂, or di(C₁ -C₄) alkylamino; phenyl optionally substituted with 1 to 3groups selected from CH₃, CH₃ O, F, Br, Cl, OH, CN, CO₂ H, CF₃, NH₂,NO₂, or di (C₁ -C₄) alkylamino; benzyl optionally substituted with 1 to3 groups selected from CH₃, CH₃ O, F, Br, Cl, OH, CN, CO₂ H, CF₃, NH₂,NO₂, or di(C₁ -C₄) alkylamino; 2-, 3-, or 4-pyridinyl, pyrimidinyl; orbiphenyl;

R⁴ is H.

More specifically preferred because of biological activity are compoundsof Formula (I) wherein:

D is N;

E is CH;

G is N;

x is S;

J is C₂ -C₁₀ alkyl.

R¹ is selected from H, CH₃ or NO₂ ;

R² is C₁ -C₈ alkyl, C₃ -C₈ branched alkyl, C₇ -C₁₄ araalkyl where thearyl group is optionally substituted with 1 to 3 groups selected fromCH₃, CH₃ O, F, NH₂, NO₂, or di(C₁ -C₄) alkylamino; phenyl optionallysubstituted with 1 to 3 groups selected from CH₃, CH₃ O, F, NH₂, NO₂, ordi(C₁ -C₄)alkylamino; benzyl optionally substituted with 1 to 3 groupsselected from CH₃, CH₃ O, F, NH₂, NO₂, or di(C₁ -C₄)alkylamino; 2-, 3-,or 4- pyridinyl, pyrimidinyl; or biphenyl;

R³ is C₁ -C₈ alkyl, C₃ -C₈ branched alkyl, C₇ -C₁₄ araalkyl where thearyl group is optionally substituted with 1 to 3 groups selected from C₁-C₄ alkyl or alkoxy, F, NH₂, NO₂, C₁ -C₄ carboalkoxy, or di(C₁ -C₄)alkylamino; phenyl optionally substituted with 1 to 3 groups selectedfrom C₁ -C₄ alkyl or alkoxy, F, NH₂, NO₂, C₁ -C₄ carboalkoxy, or di(C₁-C₄)alkylamino; benzyl optionally substituted with 1 to 3 groupsselected from C₁ -C₄ alkyl or alkoxy, F, NH₂, NO₂, C₁ -C₄ carboalkoxy,or di(C₁ -C₄)alkylamino; 2-, 3-, or 4- pyridinyl, pyrimidinyl; orbiphenyl.

Specifically preferred are:

N'-(2,4-Difluorophenyl)-N-heptyl-N-[5-(9H-purin-6-ylthio) pentyl]urea

N'-(2,4-Difluorophenyl)-N-heptyl-N-[5-(1H-pyrazolo(3,4-d)pyrimidin-4-ylthio)pentyl]urea

DETAILED DESCRIPTION OF THE INVENTION Synthesis

The novel compounds of Formula (I) may be prepared using the reactionsand techniques described in this section. The reactions are performed insolvents appropriate to the reagents and materials employed and suitablefor the transformation being effected. It is understood by those skilledin the art of organic synthesis that the functionality present on theheterocycle and other portions of the molecule must be compatible withthe reagents and reaction conditions proposed. Not all compounds ofFormula (I) falling into a given class may be compatible with some ofthe reaction conditions required in some of the methods described. Suchrestrictions to the substituents which are compatible with the reactionconditions will be readily apparent to one skilled in the art andalternative methods described must then be used.

The compounds of Formula (6) where X is O, S, or NH, can be prepared bythe route shown in Scheme 1. The compounds of Formula (1) can beprepared from a lactone or an hydroxyalkylcarboxylic acid ester ofFormula (A) or (B), respectively, where J' is a moiety having one lessmethylene group than J, and an appropriate amine, neat or in an inertsolvent such as N,N-dimethylformamide at ambient or elevatedtemperatures.

The amines of Formula (2) are prepared by reduction of the correspondingamide of Formula (1) by a variety of well known methods well known tothose skilled in the art. For example, reagents such as lithium aluminumhydride, diborane, sodium bis(2-methoxyethoxy)aluminum hydride(Red-Al®), and diisobutylaluminum hydride can be used to reduce an amideto an amine. Such reactions are typically conducted in an appropriateanhydrous aprotic solvent such as ether, toluene or tetrahydrofuran at atemperature from room temperature to the boiling point of the solventfor a period of 2-48 hours.

The compounds of Formula (3) where Y is O and Z is NR⁴, OR⁴ or R⁴, areprepared by the reaction of the secondary amines of Formula (1) with therequisite isocyanates, chloroformates, acid chlorides, activated ureasor activated carboxylic acid derivatives in an appropriate solvent suchas hexane, toluene, diethyl ether, diphenyl ether, methylene chloride ortetrahydrofuran at a temperature at or below the boiling point of thesolvent.

The guanidines of Formula (3) wherein Y is NH and Z is NHR⁴, areprepared by the reaction of the secondary amines of Formula (1) with anappropriately substituted S-methyl carbamimidothioate salt (C. R.Rasmussen, F. J. Villani, et al., Synthesis, 460, 1988), in acetonitrileor dioxane at reflux.

The compounds of Formula (4) can be prepared by conversion of thehydroxy group to a halogen moiety by a variety of well known methods.Examples of these methods are phosphorous tribromide, phosphorousoxychloride, thionyl chloride, or triphenylphosphine and carbontetrabromide. Or, compounds of Formula (4) where M is a tosylate orsimilar functionality, can be prepared from toluene sulfonyl chlorideand triethylamine, in an appropriate aprotic solvent such as methylenechloride, tetrahydrofuran or toluene.

The compounds of Formula (6) can be prepared by converting the requisitecompounds of Formula (5) where X is OH, SH or NH₂, into thecorresponding alkali metal salt by addition of a base such as sodiumhydride or potassium carbonate and alkylating with the compounds ofFormula (4) in a polar aprotic solvent such as N,N-dimethylformamide ortetrahydrofuran at an appropriate temperature.

The compounds of Formula (6) wherein J is branched alkyl, can beprepared by a route analogous to that shown in Scheme 1. The requisitelactones with branching substituents can be prepared byfunctionalization of the parent unsubstituted lactones. Alternatively,branched cyclic α,ω-diacid anhydrides can be reduced to thecorresponding branched lactone using agents such as sodium borohydride.Synthesis of compounds of Formula (4) then proceeds exactly as describedin the preceding paragraph, and alkylation of compounds of Formula (5)affords compounds of Formula (6), wherein J is branched alkyl.

The amines of Formula (6) wherein Y is H₂, are prepared by reaction ofthe corresponding ureas or amides of Formula (6) wherein Y is O, with areducing agent such as lithium aluminum hydride or other such reagentsin an appropriate anhydrous aprotic solvent such as hexane, toluene,diethylether or tetrahydrofuran at temperatures at or below the boilingpoint of the solvent. ##STR17##

The compounds of Formula (5) wherein X is SH, OH or NH₂, Scheme 1, areavailable from commercial sources or can be prepared by methods whichare well known in the chemical literature.

Alternately, the compounds of Formula (5) that are benzopyrroles of thestructure ##STR18## where D, E, and G are CR¹ and X is OH, SH or NH₂,Scheme 2, can be synthesized from the correspondingo-amino-ω-chlorostyrene of Formula (7) upon treatment with a base suchas sodium ethoxide in a suitable solvent such as ethanol to givecompounds of Formula (8). ##STR19##

The compounds of Formula (1) that are benzopyrazoles orpyrazolopyridines of the structure ##STR20## where D, E, and G are CR¹or N with no more than one nitrogen per ring and X is OH, SH or NH₂,Scheme 3, can be synthesized upon heating of the correspondingo-hydrazinocinnamic acid of Formula (9) in a suitable solvent such asbenzene to give compounds of Formula (10). ##STR21##

The compounds of Formula (5) that are benzimidazoles or imidazopyridinesof the structure ##STR22## where D, E, and G are CR¹ or N with no morethan one nitrogen per ring and X is OH, SH or NH₂, Scheme 4, can besynthesized upon heating of the corresponding o-phenylenediamine offormula (11) and formic acid in a suitable solvent such asN,N-dimethylformamide to give compounds of Formula (12). ##STR23##

The compounds of Formula (5) that are pyrrolopyridines of the structure##STR24## where D, E and G are CR¹ or N with no more than one nitrogenper ring and X is OH, SH or NH₂, Scheme 5, can be synthesized uponcyclization of the corresponding formamidomethylpicoline of Formula (13)using sodium anilide and potassium formate to give compounds of Formula(14). ##STR25##

The compounds of Formula (5) that are pyrrolopyridazines of thestructure ##STR26## where D is CR¹ and X is OH, SH or NH₂, Scheme 6, canbe synthesized upon heating of the corresponding 2-formyl-3-acylpyroleof Formula (15) with hydrazine to give compounds of Formula (16).##STR27##

The compounds of Formula (5) that are pyrazolopyridazines of thestructure ##STR28## where D is CR¹ and X is OH, SH or NH₂, Scheme 7, canbe synthesized upon heating the corresponding5-chloro-4-hydroxymethylpyridazine of Formula (17) with hydrazine withsubsequent treatment with nitrous acid to give compounds of Formula(18). ##STR29##

The compounds of Formula (5) that are imidazopyridazines of thestructure ##STR30## where D is CR¹ and X is OH, SH or NH₂, Scheme 8, canbe synthesized upon heating of the corresponding pyridazinediamine ofFormula (19) and formic acid in a suitable solvent such asN,N-dimethylformamide to give compounds of Formula (20). ##STR31##

The compounds of Formula (5) that are pyrrolopyrimidines of thestructure ##STR32## where E is CR¹ and X is OH, SH, NH₂, Scheme 9, canbe synthesized from the corresponding o-amino-ω-chlorostyrene of Formula(21) upon treatment with a base such as sodium ethoxide in a suitablesolvent such as ethanol to give compounds of Formula (22). ##STR33##

The compounds of Formula (5) that are pyrazolopyrimidines of thestructure ##STR34## where E is CR¹ and X is OH, Scheme 10, can besynthesized from aminopyrazolocarboxyamide of Formula (23) and theappropriately substituted formamide of Formula (24) in a suitablesolvent such as N,N-dimethylformamide to give compounds of Formula (25).##STR35##

The compounds of Formula (5) that are pyrazolopyrimidines of thestructure ##STR36## where E is CR¹ and X is SH, Scheme 11, can besynthesized from the corresponding 4-hydroxypyrazolopyrimidine ofFormula (25) and phosphorous pentasulfide to give compounds of Formula(26). ##STR37##

The compounds of Formula (5) that are pyrazolopyrimidines of thestructure ##STR38## where E is CR¹ and X is NH₂, Scheme 12, can besynthesized from the corresponding 4-hydroxypyrazolopyrimidine ofFormula (25) and phosphoryl chloride to give the corresponding4-chloropyrazolopyrimidine of Formula (27) which is then treated withammonia to give compounds of Formula (28). ##STR39##

The compounds of Formula (5) that are purines of the structure ##STR40##where E is CR¹ and X is OH or NH₂, Scheme 13, can be synthesized fromthe corresponding 4,5-diaminopyrimidines of Formula (29) and formic acidin a suitable solvent such as pyridine, N,N-dimethylformamide, or1-propanol to give compounds of Formula (30). ##STR41##

The compounds of Formula (5) that are purines of the structure ##STR42##where E is CR¹ and X is SH, Scheme 14, can be synthesized from thecorresponding 6-hydroxypurines of Formula (30) where X is O, andphosphorous pentasulfide in a suitable solvent such as benzene to givecompounds of Formula (31). ##STR43##

The compounds of Formula (5) that are pyrrolopyridazines of thestructure ##STR44## where G is CR¹ and X is OH, SH or NH₂, Scheme 15,can be synthesized from the corresponding 3-amino-ω-chlorostyrene ofFormula (32) upon treatment with a base such as sodium ethoxide in asuitable solvent such as ethanol to give compounds of Formula (33).##STR45##

The compounds of Formula (5) that are pyrazolopyridazines of thestructure ##STR46## where G is CR¹ and X is OH, SH or NH₂, Scheme 16,can be synthesized upon heating the corresponding3-chloro-4-hydroxymethylpyridazine of Formula (34) with hydrazine withsubsequent treatment with nitrous acid to give compounds of Formula(35). ##STR47##

The compounds of Formula (5) that are imidazopyridazines of thestructure ##STR48## where G is CR¹ and X is OH, SH or NH₂, Scheme 17,can be synthesized upon heating of the corresponding pyridazinediamineof Formula (36) and formic acid in a suitable solvent such asN,N-dimethylformamide to give compounds of Formula (37). ##STR49##

The compounds of Formula (6) wherein X is CH₂, can be prepared by theroute shown in Scheme 18. The corresponding chloro-substituted compoundsof Formula (38) can be converted to the cyano-substituted compounds ofFormula (39) by treatment with as cuprous cyanide or sodium cyanide in asolvent such as dimethyl sulfoxide. This is a general reaction of ahalide (Cl, Br, I) which involves nucleophilic substitution by a widevariety of substitutients (P. Herdewijin, Synthesis, 1989, 961). Thenitriles of Formula (39) can be hydrolyzed to the correspondingcarboxylic acid of Formula (40) upon heating in aqueous alkali or acid.The carboxylic acids of Formula (40) can be reduced to the correspondingalcohol of Formula (41) upon treatment with lithium aluminum hydride inan appropriate anhydrous aprotic solvent such as tetrahydrofuran ortoluene at a temperature at or below the boiling point of the solvent.The alcohols of Formula (41) can be converted to the correspondingaldheyde upon treatment with potassium dichromate under acidicconditions to give compounds of Formula (42). The aldehydes of Formula(42) can be converted to the corresponding compounds of Formula (44) viathe Wittig Reaction using an appropriate phosphoylide of Formula (43)prepared from the desired bromoalkylamine and triphenylphosphene. Thecompounds of Formula (44) can be converted to the correspondingcompounds of Formula (45) via catalytic hydrogenation using a catalystsuch as palladium on activated carbon in a solvent such as ethanol. Thecompounds of Formula (45) can be converted to the compounds of Formula(6) upon treatment with the requisite isocyanate, chloroformate, acidchloride or other activated carboxylic acid derivative as previouslydescribed.

Likewise, compounds of Formula (6) wherein X is O, S, NH or CH₂ and Y isH₂, can be prepared by reacting compounds similar to compounds ofFormula (45) with an appropriately functionalized secondary amine HN(CH₂Z)R³, in a solvent such as toluene, acetonitrile, tetrahydrofuran, orN,N-dimethylformamide at a temperature at or below the boiling point ofthe solvent. ##STR50##

As shown in Scheme 19, the thioureas or thioamides of Formula (47) whereY is S and Z is NHR⁴ or R⁴, can be prepared from the corresponding ureasor amides of Formula (46) by the reaction with Lawesson's reagent ordiphosphorus pentasulfide in an appropriate solvent such as toluene.##STR51##

As shown in Scheme 20, the compounds of Formula (I) wherein X isS(O)_(r) and r is 1 or 2, can be prepared by the oxidation of thecompounds of Formula (48) by methods which are well known in thechemical literature. For example, the oxidation of compounds of Formula(48) with one equivalent of a peracid such as m-chloroperoxybenzoic acidin a suitable solvent such as methylene chloride at a low temperatureaffords primarily the sulfoxides of Formula (49), and the oxidation ofcompounds of Formula (48) with an oxidant such as potassium hydrogenpersulfate, or Oxone®, in a suitable solvent such as methanol affordsthe sulfones of Formula (50). ##STR52##

Preparation of pharmaceutically suitable salts of Formula (I) can becarried out in accordance with well known techniques for forming salts.Physiologically acceptable salts include acid addition salts, e.g.,hydrochloric, sulfuric, acetic, trifluoroacetic, succinic, citric, andbenzene sulfonic acid salts.

The compounds of this invention and their preparation can be furtherunderstood by the following examples, which exemplify but do notconstitute a limitation of the invention. In these examples, unlessotherwise indicated, all temperatures are in degrees centigrade andparts and percentages are by weight.

EXAMPLE 1 Preparation ofN'-(2,4-difluorophenyl)-N-heptyl)-N-[5-(9H-purin-6-ylthio)pentyl]urea

Part A. A solution of γ-valerolactone (25.0 g, 0.249 mol) in toluene (50mL) and n-heptylamine (35.96 g, 0.312 mol) was heated to reflux for 18hours under a nitrogen atmosphere. The reaction mixture was allowed tocool to ambient temperature, diluted with ethyl acetate (300 mL), washedwith 1 N aqueous HCl (50 mL), water and brine. The organic layer wasdried over magnesium sulfate and concentrated to give a white solid. Theproduct was crystallized from ethyl ether:hexane to giveN-heptyl-5-hydroxypentanamide (41.8 g, 0.194 mol) as white plates, mp55°-56°. ¹ H NMR (CDCl₃) δ6.06 (bs, 1H), 3.61 (t,2H, J=7.3 Hz), 3.24(quartet,2H,J=8.4 Hz), 3.19 (bs, 1H), 2.19 (t,2H, J=8.3 Hz), 1.80-1.23(m, 14H), 0.86 (t,3H, J=6.0 Hz).

Part B. To a solution of lithium aluminum hydride (6.7 g, 0.176 mol) indry tetrahydrofuran (300 mL), a solution ofN-heptyl-5-hydroxypentanamide (19.0 g, 0.088 mol) in dry tetrahydrofuran(100 mL) under a nitrogen atmosphere was added dropwise. The reactionmixture was heated to reflux for 18 hours, allowed to cool to roomtemperature and was poured slowly into a stirred mixture of 10% aqueoussodium sulfate (400 mL) and ice (200 mL). The resulting slurry wasfiltered through a bed of Celite® and the filtrate was extracted withethyl acetate (2×500 mL). The combined organic extracts were washed withwater and brine, then dried over magnesium sulfate and concentrated togive a viscous yellow oil. The product was crystallized from hexane togive N-(5-hydroxypentyl)-N-heptylamine (15.2 g, 0.075 mol) as a whitepowder, mp 47°-48°. ¹ H NMR (CDCl₃) δ3.63 (t,2H, J=8.4 Hz), 2.63(quartet,4H,J=8.3 Hz), 2.39 (bs,2H), 1.66-1.24 (m, 16H), 0.91(t,3H,J=6.6 Hz).

Part C. To a solution of N-(5-hydroxypentyl)-N-heptylamine (11.65 g,0.0578 mol) in methylene chloride (75 mL) under a nitrogen atmospherecooled to 0°, 2,4-difluorophenylisocyanate (8.97 g, 0. 0578 mol) wasadded slowly. The reaction mixture was stirred for 1 hour, poured into 1N aqueous HCl (200 mL) and extracted with ethyl acetate (300 mL). Thecombined organic extracts were washed with water and brine, then driedover magnesium sulfate and was concentrated to giveN'-{2,4-difluorophenyl)-N-heptyl-N-5-hydroxypentylurea as a pale yellowoil (20.0 g, 0.056 mol). ¹ H NMR (CDCl₃) δ8.03 (m, 1H), 6.88-6.59 (m,2H), 6.45 (bs, 1H), 3.68 (t, 2H, J=8.4 Hz), 3.33 (m, 4H), 1.81-1.22 (m,16H), 0.91 (t,3H, J=6.7 Hz).

Part D. To a solution of N'-(2,4-difluorophenyl)-N-heptyl-N-5-hydroxypentylurea (15.0 g, 0.042 mol) and carbontetrabromide (16.75 g, 0.051 mol) in methylene chloride (350 mL) under anitrogen atmosphere at ambient temperature, a solution oftriphenylphosphine (13.24 g, 0.051 mol) in methylene chloride (100 mL)was added slowly. The reaction mixture was stirred for 3 hours and thenconcentrated in vacuo to give crude viscous oil. The product waspurified by flash chromatography on silica gel (400 mL) eluting withhexane:ethyl acetate (90:10::v:v) to giveN-(5-bromopentyl)-N'-(2,4-difluorophenyl)-N-heptylurea as a viscouscolorless oil (17.5 g, 0.042 mol). ¹ H NMR (CDCl₃) δ8.14-8.00 (m, 1H),6.92-6.79 (m, 2H), 6.35 (bs, 1H), 3.49-3.25 (m, 6H), 1.99-1.26 (m, 16H),0.92 (t,3H, J=6.7 Hz).

Part E. To a suspension of sodium hydride (0.04 g, 60% mineral oildispersion, 0.001 mol; washed free of mineral oil with hexane) andsodium iodide (0.04 g, 0.0003 mol) in N,N-dimethylformamide (10 mL)under a nitrogen atmosphere, cooled to 0°, a solution of6-mercaptopurine monohydrate (0.17 g, 0.001 mol) inN,N-dimethylformamide (5 mL) was added slowly. The reaction mixture wasstirred for 30 minutes and then a solution ofN-(5-bromopentyl)-N'-(2,4-difluorophenyl)-N-heptylurea (0.42 g, 0.001mol) in N,N-dimethylformamide (5 mL) was added. The reaction mixture wasstirred for 30 minutes and then allowed to warm to ambient temperatureand stirred an additional 120 hours. The reaction mixture was pouredinto water (50 mL) and extracted with ethyl acetate (2×50 mL). Thecombined organic extracts were washed with water and brine, then driedover magnesium sulfate and concentrated to give a viscous oil. Theproduct was purified by flash chromatography on silica gel eluting withhexane:ethyl acetate (50:50: :v:v) to give the title compound (0.31 g,0.00063 mol) as a pure white solid, mp=87°-89°. ¹ H NMR (CDCl₃) δ8.9 (s,1H), 8.2 (s,1H), 8.1-8.0 (m, 1H), 6.9-6.8 (m, 2H), 6.5 (s, 1H), 3.5-3.2(m, 6H), 1.9-1.2 (m, 17H), 0.9-0.8 (m, 3H).

EXAMPLE 2 Preparation ofN'-(2,4-difluorophenyl)-N-heptyl-N-[5-(1H-pyrazolo(3,4-d)pyrimidin-4-ylthio)pentyl]urea

Employing the method of Example 1, Part E, but using4-mercapto-1-pyrazolopyrimidine (0.15 g, 0.001 mol), the title compound(0.39 g, 0.00079 mol) was isolated as a viscous oil. ¹ H NMR (CDCl₃)δ8.75 (s, 1H), 8.1-8.0 (m, 2H), 7.9-7.8 (m, 2H), 6.5-6.4 (m, 1H),3.4-3.2 (m, 6H), 1.9-1.2 (m, 18H), 0.9-0.8 (m, 3H).

EXAMPLE 3 Preparation ofN-heptyl-N'-(1-methylethyl)-N-[5-(9H-purin-6-ylthio)pentyl]urea

To a solution of 2-mercaptopurine monohydrate (0.41 g, 0.0024 mol) andpotassium carbonate (0.33 g, 0.0024 mol) and sodium iodide (0.03 g) indry tetrahydrofuran (10 mL) was added, dropwise, a solution ofN-(5-bromopentyl)-N'-(1-methylethyl)-N-heptylurea (0.84 g, 0.0024 mol)in dry tetrahydrofuran (5 mL). The reaction mixture was stirred at55°-60° for 20 hours. The reaction mixture was poured into water andextracted with ethyl acetate. The organic layer was dried over magnesiumsulfate and concentrated. The residue was purified by flashchromatography using ethyl acetate to give the title compound (0.56 g,0.0013 mol) as a clear, viscous oil. ¹ H NMR (CDCl₃) δ8.75 (s, 1H), 8.2(s, 1H), 4.2-3.9 (m, 2H), 3.5-3.3 (m, 2H), 3.3-3.1 (m, 4H), 1.9-1.1 (m,23H), 0.9-0.8 (m, 3H).

EXAMPLE 4 Preparation of N-heptyl-N'-(1-methylethyl)-N-[5-(1H-pyrazolo(3,4-d)pyrimidin-4-ylthio)pentyl]urea

Employing the method of Example 3, but using4-mercapto-1-pyrazolopyrimidine (0.37 g; 0.0024 mol), the title compound(0.70 g, 0.0017 mol) was isolated as a pale yellow solid, mp=81°-83°. ¹H NMR (CDCl₃) δ8.8 (s, 1H), 8.1 (s, 1H), 4.1-3.9 (m, 2H), 3.4 (t, 2H,J=7.4Hz), 3.2 (t,2H, J=6.3Hz), 3.1 (t,2H, J=7.5Hz), 1.8 (quintet,2H,J=7.3Hz), 1.7-1.2 (m, 15H), 1.15 (d, 6H,J=6.3Hz), 0.9 (t, 3H, J=6.1Hz).

EXAMPLE 5 Preparation of phenylN-[5-(9H-purin-6-ylthio)pentyl]-N-heptylcarbamate

Employing the method of Example 3, but using phenylN-(5-bromopentyl)-N-heptylcarbamate (0.92 g, 0. 0024 mol), the titlecompound (0.48 g, 0.0011 mol) was isolated as an oil. ¹ H NMR (CDCl₃)δ12.15 (bs, 1H), 8.75 (s, 1H), 8.1 (s,1H), 7.4-7.3 (m, 2H), 7.2-7.0 (m,3H), 3.5-3.2 (m, 7H), 1.95-1.2 (m, 15H), 0.9-0.8 (m, 3H).

EXAMPLE 6 Preparation of phenylN-[5-(1H-pyrazolo(3,4-d)pyrimidin-4-ylthio)pentyl]-N-heptylcarbamate

Employing the method of Example 5, but using4-mercapto-1-pyrazolopyrimidine (0.37 g, 0.0024 mol), the title compound(1.10 g, 0.0024 mol) was isolated as a clear yellow oil. ¹ H NMR (CDCl₃)δ12.0 (bs, 1H), 8.8 (s, 1H), 8.15 (s, 1H), 7.4-7.05 (m, 5H), 3.5-3.25(m, 6H), 1.95-1.45 (m, 8H), 1.4-1.2 (m, 8H), 0.85 (t, 3H, J=6.6Hz).

    TABLE 1      ##STR53##                 Data EX. A B D E G X J R.sup.3 Y Z (mp °C.)        1 N CH N CH N S CH.sub.2 (CH.sub.2).sub.3 CH.sub.2 (CH.sub.2).sub.6     CH.sub.3 O NH-2,4-diFC.sub.6 H.sub.3 87-89  2 CH N N CH N S CH.sub.2     (CH.sub.2).sub.3 CH.sub.2 (CH.sub.2).sub.6 CH.sub.3 O NH-2,4-diFC.sub.6     H.sub.3 oil.sup.(a)  3 N CH N CH N S CH.sub.2 (CH.sub.2).sub.3 CH.sub.2     (CH.sub.2).sub.6 CH.sub.3 O NHCH(CH.sub.3).sub.2 oil.sup.(b)  4 CH N N     CH N S CH.sub.2 (CH.sub.2).sub.3 CH.sub.2 (CH.sub.2).sub.6 CH.sub.3 O     NHCH(CH.sub.3).sub.2 81-83  5 N CH N CH N S CH.sub.2 (CH.sub.2).sub.3     CH.sub.2 (CH.sub.2).sub.6 CH.sub.3 O OC.sub.6 H.sub.5 oil.sup.(c)  6 CH     N N CH N S CH.sub.2 (CH.sub.2).sub.3 CH.sub.2 (CH.sub.2).sub.6 CH.sub.3     O OC.sub.6 H.sub.5 oil.sup.(d)  7 N CH N CH N S CH.sub.2      CH(CH.sub.3)(CH.sub.2).sub.3 CH.sub.3 O NH-2,4-diOHC.sub.6 H.sub.3  8 N     CH N CH N SO (CH.sub.2).sub.3 CH(CH.sub.3)CH.sub.2 CH.sub.2      CH(CH.sub.3).sub.2 S NH-4-CNC.sub.6 H.sub.4  9 N CH N FC N SO.sub.2     (CH.sub.2).sub.3 C(CH.sub.3).sub.2 CH.sub.2 CH.sub.2C.sub.6 H.sub.11     H.sub.2 NH-2,4,6-triCF.sub.3C.sub.6 H.sub.2 10 N CF.sub.3C N CH N S     (CH.sub.2).sub.2 CH(C.sub.5 H.sub.11 )(CH.sub.2).sub.2 CH.sub.2      CH.sub.2C.sub.6 H.sub.5 NH CH.sub.2 CH(CH.sub.3).sub.2 11 N CH N     CH.sub.3 OC N S CH(CH.sub.3)(CH.sub.2).sub.4 2,4-diFC.sub.6 H.sub.3 O     CH.sub.2C.sub.6 H.sub.11 12 N CNC N CH N O CH.sub.2 CHCH(CH.sub.2).sub.2     CH.sub.2 CHCH(CH.sub.2).sub.2 CH.sub.3 O CH.sub.2      -2,6-diCH(CH.sub.3).sub.2C.sub.6 H.sub.3 13 N CH.sub.3 SC N CH N NH     (CH.sub.2).sub.3 CHCH(CH.sub.2).sub.2 CH.sub.2 CC(CH.sub.2).sub.2     CH.sub.3 O O(CH.sub.2).sub.7 CH.sub.3 14 N CH N CH N CH.sub.2 CH.sub.2     CC(CH.sub.2).sub.2 CH.sub.2 -2,4-diOHC.sub.6 H.sub.3 S OCH.sub.2C.sub.6     H.sub.11 15 N CH N CH N SO (CH.sub.2).sub.3      CC(CH.sub.2).sub.2 4-CH.sub.3 OC.sub.6 H.sub. 4 S OCF.sub.2 CF.sub.2     CF.sub.3 16 N CH N (CH.sub.3).sub.2 CHC N NH CH.sub.2 (CH.sub.2).sub.4     CH.sub.2 2,4,6-triCF.sub.3C.sub.6      H.sub.2 H.sub.2 NH(CH.sub.2).sub.2C.sub.6 H.sub.5 17 CH N N CH N S     CH.sub.2 CH(CH.sub.3)(CH.sub.2).sub.3 CH.sub.2 -4-pyridinyl S CH.sub.2     CC(CH.sub.2).sub.2 CH.sub.3 18 CH.sub.3 SC N N CH N S CH.sub.2      CHCH(CH.sub.2).sub.2 CH.sub.3 O CH.sub.2C.sub.6 H.sub.5 19 CH N N CH N     SO (CH.sub.2).sub.3 CHCH(CH.sub.2).sub.2 CH.sub.2 CH(CH.sub.3).sub.2 O     C.sub.6 H.sub.5 20 CH N N CH N S CH.sub.2      CC(CH.sub.2).sub.2 CH.sub.2C.sub.6 H.sub.11 S CH.sub.2C.sub.6 H.sub.5     21 CH.sub.3 (CH.sub.2).sub.7C N N CH N SO.sub.2 (CH.sub.2).sub.3     C C(CH.sub.2).sub.2 CH.sub.2 CH.sub.2C.sub.6      H.sub.5 S OCH(CH.sub.3).sub.2 22 CH.sub.3 CH.sub.2OC N N CH N SO.sub.2     CH.sub.2 (CH.sub.2).sub.7 CH.sub.2 CH.sub.2 -4-CO.sub.2 HC.sub.6 H.sub.4     O NH-3-pyridinyl 23 N CH FC N N S CH.sub.2 (CH.sub.2).sub.6 CH.sub.2     2,4,6-triCF.sub.3C.sub.6 H.sub.2 O CH.sub.2 -2,4,6-triCH.sub.3 OC.sub.6     H.sub.2 24 N CH CH.sub.3C N N SO CH.sub.2 (CH.sub.2).sub.7 CH.sub.2     CH.sub.2 -4-CO.sub.2 HC.sub.6 H.sub.4 O NH-3-pyridinyl 25 N CH CH N N     SO.sub.2 CH.sub.2 (CH.sub.2).sub.8 CH.sub.2 2,6-diCH.sub.3 OC.sub.6     H.sub.3 O CH.sub.2 -2-pyrimidinyl 26 N CNC CH N N S CH.sub.2      CH(CH.sub.3)(CH.sub.2).sub.3 CH.sub.3 O NH-2,4-diOHC.sub.6 H.sub.3 27 N     CH CH N N SO (CH.sub.2).sub.3 CH(CH.sub.3)CH.sub.2 CH.sub.2      CH(CH.sub.3).sub.2 S NH-4-CNC.sub.6      H.sub.4 28 N CH CH N N S CH(CH.sub.3 )(CH.sub.2).sub.4 2,4-diFC.sub.6     H.sub.3 O CH.sub.2C.sub.6 H.sub.11 29 N CH CH N N SO CH.sub.2      CHCH(CH.sub.2).sub.2 CH.sub.2 CHCH(CH.sub.2).sub.2 CH.sub.3 O CH.sub.2     -2,6-diCH(CH.sub.3).sub.2C.sub.6 H.sub.3 30 N CH CH N N SO.sub.2     (CH.sub.2).sub.3 CHCH(CH.sub.2).sub.2 CH.sub.2 CC(CH.sub.2).sub.2     CH.sub.3 O O(CH.sub.2)7CH.sub.3 31 N CH CH N N S CH.sub.2      CC(CH.sub.2).sub.2 CH.sub.2 -2,4-diOHC.sub.6 H.sub.3 S OCH.sub.2C.sub.6     H.sub.11 32 N NH.sub.2C CH N N SO (CH.sub.2).sub.3 CC(CH.sub.2).sub.2     4-CH.sub.3 OC.sub.6 H.sub.4 S OCF.sub.2 CF.sub.2 CF.sub.3 33 CH N     CH.sub.3C N N S CH.sub.2 (CH.sub.2).sub.6 CH.sub.2 CH.sub.2      -4-(CH.sub.3).sub.2 NC.sub.6 H.sub.4 O CH.sub.2 -4-(CH.sub.3).sub.2     NC.sub.6 H.sub.4 34 CH N CH N N S CH.sub.2 (CH.sub.2).sub.7 CH.sub.2     CH.sub.2 -3-pyridinyl O CH.sub.2 CHCH(CH.sub.2).sub.2 CH.sub.3 35 CH N     CH N N SO CH.sub.2 (CH.sub.2).sub.8 CH.sub.2 CH.sub.2 -2-pyrimidinyl S     OC.sub.6 H.sub.5 36 CH N CH N N S CH.sub.2 CH(CH.sub.3)(CH.sub.2).sub.3     CH.sub.2 -4-pyridinyl S CH.sub.2 CC(CH.sub.2).sub.2 CH.sub.3 37 CH N CH     N N S CH.sub.2 CHCH(CH.sub.2).sub.2 CH.sub.3 O CH.sub.2C.sub.6 H.sub.5     38 CH N CH N N SO (CH.sub.2).sub.3 CHCH(CH.sub.2).sub.2 CH.sub.2     CH(CH.sub.3).sub.2 O C.sub.6 H.sub.5 39 NH.sub.2C N CH N N SO.sub.2     CH.sub.2 CC(CH.sub.2).sub.2 CH.sub.2C.sub.6 H.sub.11 S CH.sub.2C.sub.6     H.sub.5 40 N CH N N F C SO.sub.2 CH.sub.2 (CH.sub.2).sub.6 CH.sub.2     2,4,6-triCF.sub.3C.sub.6 H.sub.2 O CH.sub.2 -2,4,6-triCH.sub.3 OC.sub.6     H.sub.2 41 N CNC N N CH S CH.sub.2 CH(CH.sub.3)(CH.sub.2).sub.3 CH.sub.3     O NH-2,4-diOHC.sub.6 H.sub.3 42 N CH N N CH SO (CH.sub.2).sub.3      CH(CH.sub.3)CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2 S NH-4-CNC.sub.6     H.sub.4 43 N CH.sub.3 (CH.sub.2).sub.7C N N CH S CH(CH.sub.3)(CH.sub.2)4     2,4-diFC.sub.6 H.sub.3 O CH.sub.2C.sub.6 H.sub.11 44 N CH N N CH     SO.sub.2 CH.sub.2 CHCH(CH.sub.2).sub.2 CH.sub.2 CHCH(CH.sub.2).sub.2     CH.sub.3 O CH.sub.2 -2,6-diCH(CH.sub.3).sub.2C.sub.6 H.sub.3 45 N CH N N     CH S (CH.sub.2).sub.3 CHCH(CH.sub.2).sub.2 CH.sub.2 CC(CH.sub.2).sub.2     CH.sub.3 O O(CH.sub.2).sub.7 CH.sub.3 46 N CH N N CH SO CH.sub.2     C (CH.sub.2).sub.2 CH.sub.2 -2,4-diOHC.sub.6 H.sub.3 S OCH.sub.2C.sub.6     H.sub.11 47 N CH N N NH.sub.2C SO (CH.sub.2).sub.3 CC(CH.sub.2).sub.2     4-CH.sub.3 OC.sub.6 H.sub.4 S OCF.sub.2 CF.sub.2 CF.sub.3 48 CH N N N     CH.sub.3C SO CH.sub.2 (CH.sub.2).sub.6 CH.sub.2 CH.sub.2      -4-(CH.sub.3).sub.2 NC.sub.6 H.sub.4 O CH.sub.2 -4-(CH.sub.3).sub.2     NC.sub.6 H.sub.4 49 CH.sub.3 OC N N N CH S CH.sub.2 (CH.sub.2).sub.7     CH.sub.2 CH.sub.2 -3-pyridinyl O CH.sub.2 CHCH(CH.sub.2).sub.2 CH.sub.3     50 CH N N N CH SO.sub.2 CH.sub.2 (CH.sub.2).sub.8 CH.sub.2 CH.sub.2     -2-pyrimidinyl S OC.sub.6 H.sub.5 51 CH N N N CH S CH.sub.2      CH(CH.sub.3)(CH.sub.2).sub.3 CH.sub.2 -4-pyridinyl S CH.sub.2      CC(CH.sub.2).sub.2 CH.sub.3 52 CH N N N CH SO.sub.2 CH.sub.2      CHCH(CH.sub.2).sub.2 CH.sub.3 O CH.sub.2C.sub.6 H.sub.5 53 CH N N N CH     SO (CH.sub.2).sub.3 CHCH(CH.sub.2).sub.2 CH.sub.2 CH(CH.sub.3).sub.2 O     C.sub.6 H.sub.5 54 CH N N N NH.sub.2C S CH.sub.2 CC(CH.sub.2).sub.2     CH.sub.2C.sub.6 H.sub.11 S CH.sub.2C.sub.6 H.sub.5 55 CH N N N CH     SO.sub.2 (CH.sub.2).sub.3 CC(CH.sub.2).sub.2 CH.sub.2 CH.sub.2C.sub.6     H.sub.5 S OCH(CH.sub.3).sub.2 56 N CH N CH CH S CH.sub.2      (CH.sub.2).sub.6 CH.sub.2 2,4,6-triCF.sub.3C.sub.6 H.sub.2 O CH.sub.2     -2,4,6-triCH.sub.3 OC.sub.6 H.sub.2 57 N CH CH N CH SO.sub.2 CH.sub.2     (CH.sub.2).sub.8 CH.sub.2 2,6-diCH.sub.3 OC.sub.6 H.sub.3 O CH.sub.2     -2-pyrimidinyl 58 N CH CH N CH S CH.sub.2 CH(CH.sub.3)(CH.sub.2).sub.3     CH.sub.3 O NH-2,4-diOHC.sub.6      H.sub.3 59 N CH CH N CH SO (CH.sub.2).sub.3 CH(CH.sub.3)CH.sub.2     CH.sub.2 CH(CH.sub.3).sub.2 S NH-4-CNC.sub.6 H.sub.4 60 N CH CH CH N S     CH(CH.sub.3)(CH.sub.2)4 2,4-diFC.sub.6 H.sub.3 O CH.sub.2C.sub.6     H.sub.11 61 N CH CH CH N SO CH.sub.2 CHCH(CH.sub.2).sub.2 CH.sub.2     CHCH(CH.sub.2).sub.2 CH.sub.3 O CH.sub.2      -2,6-diCH(CH.sub.3).sub.2C.sub.6      H.sub.3 62 N CH CH CH N S (CH.sub.2).sub.3 CHCH(CH.sub.2).sub.2     CH.sub.2 CC(CH.sub.2).sub.2 CH.sub.3 O O(CH.sub.2).sub.7 CH.sub.3 63 CH     N N CH CH SO.sub.2 CH.sub.2 CC(CH.sub.2).sub.2 CH.sub.2 -2,4-diOHC.sub.6     H.sub.3 S OCH.sub.2C.sub.6 H.sub.11 64 CH N N CH CH SO (CH.sub.2).sub.3    C     C(CH.sub.2).sub.2 4-CH.sub.3 OC.sub.6 H.sub.4 S OCF.sub.2 CF.sub.2     CF.sub.3 65 CH N CH N CH SO.sub.2 CH.sub.2 (CH.sub.2).sub.6 CH.sub.2     CH.sub.2 -4-(CH.sub.3).sub.2 NC.sub.6 H.sub.4 O CH.sub.2      -4-(CH.sub.3).sub.2 NC.sub.6 H.sub.4 66 CH N CH N CH S CH.sub.2     (CH.sub.2).sub.7 CH.sub.2 CH.sub.2 -3-pyridinyl O CH.sub.2      CHCH(CH.sub.2).sub.2 CH.sub.3 67 CH N CH CH N SO CH.sub.2      (CH.sub.2).sub.8 CH.sub.2 CH.sub.2 -2-pyrimidinyl S OC.sub.6 H.sub.5 68     CH N CH CH N S CH.sub.2 CH(CH.sub.3)(CH.sub.2).sub.3 CH.sub.2      -4-pyridinyl S CH.sub.2 CC(CH.sub.2).sub.2 CH.sub.3 69 CH N CH CH CH     SO.sub.2 CH.sub.2 CHCH(CH.sub.2).sub.2 CH.sub.3 O CH.sub.2C.sub.6     H.sub.5 70 CH N CH CH CH SO (CH.sub.2).sub.3 CHCH(CH.sub.2).sub.2     CH.sub.2 CH(CH.sub.3).sub.2 O C.sub. 6 H.sub.5 71 N CH CH CH CH S     CH.sub.2 CC(CH.sub.2).sub.2 CH.sub.2C.sub.6 H.sub.11 S CH.sub.2C.sub.6     H.sub.5 72 N CH CH CH CH SO.sub.2 (CH.sub.2).sub.3 CC(CH.sub.2).sub.2     CH.sub.2 CH.sub.2C.sub.6 H.sub.5 S OCH(CH.sub.3).sub.2 73 CH CH N CH N     SO CH.sub.2 (CH.sub.2).sub.6 CH.sub.2 2,4,6-triCF.sub.3C.sub.6 H.sub.2 O     CH.sub.2 -2,4,6-triCH.sub.3 OC.sub.6 H.sub.2 74 CH CH N CH N S CH.sub.2     (CH.sub.2).sub.7 CH.sub.2 CH.sub.2 -4-CO.sub.2 HC.sub.6 H.sub.4 O     NH-3-pyridinyl 75 CH CH CH N N SO.sub.2 CH.sub.2 (CH.sub.2).sub.8     CH.sub.2 2,6-diCH.sub.3 OC.sub.6 H.sub.3 O CH.sub.2 -2-pyrimidinyl 76 CH     CH CH N N S CH.sub.2      CH(CH.sub.3)(CH.sub.2).sub.3 CH.sub.3 O NH-2,4-diOHC.sub.6 H.sub.3 77     CH CH CH N N SO (CH.sub.2).sub.3 CH(CH.sub. 3)CH.sub.2 CH.sub.2      CH(CH.sub.3).sub.2 S NH-4-CNC.sub.6      H.sub.4 78 CH CH N N CH S CH(CH.sub.3)(CH.sub.2).sub.4 2,4-diFC.sub.6     H.sub.3 O CH.sub.2C.sub.6 H.sub.11 79 CH CH N N CH SO CH.sub.2      CHCH(CH.sub.2).sub.2 CH.sub.2 CH(CH.sub.2).sub.2 CH.sub.3 O CH.sub.2     -2,6-diCH(CH.sub.3).sub.2C.sub.6      H.sub.3 80 CH CH N N CH S (CH.sub.2).sub.3 CHCH(CH.sub.2).sub.2     CH.sub.2 CC(CH.sub.2).sub.2 CH.sub.3 O O(CH.sub.2).sub.7 CH.sub.3 81 CH     CH N CH CH SO.sub.2 CH.sub.2 CC(CH.sub.2).sub.2 CH.sub.2      -2,4-diOHC.sub.6 H.sub.3 S OCH.sub.2C.sub.6 H.sub.11 82 CH CH N CH CH     SO (CH.sub.2).sub.3 CC(CH.sub.2).sub.2 4-CH.sub.3 OC.sub.6 H.sub.4 S     OCF.sub.2 CF.sub.2 CF.sub.3 83 CH CH CH N CH SO.sub.2 CH.sub.2      (CH.sub.2).sub.6 CH.sub.2 CH.sub.2 -4-(CH.sub.3).sub.2 NC.sub.6 H.sub.4     O CH.sub.2 -4-(CH.sub.3).sub.2 NC.sub.6 H.sub.4 84 CH CH CH N CH S     CH.sub.2 (CH.sub.2).sub.7 CH.sub.2 CH.sub.2 -3-pyridinyl O CH.sub.2     CHCH(CH.sub.2).sub.2 CH.sub.3 85 CH CH CH CH N SO CH.sub.2      (CH.sub.2).sub.8 CH.sub.2 CH.sub.2 -2-pyrimidinyl S OC.sub.6 H.sub.5 86     CH CH CH CH N S CH.sub.2 CH(CH.sub.3)(CH.sub.2).sub.3 CH.sub.2      -4-pyridinyl S CH.sub.2 CC(CH.sub.2).sub.2 CH.sub.3 87 CH CH CH CH CH S     CH.sub.2 CHCH(CH.sub.2).sub.2 CH.sub.3 O CH.sub.2C.sub.6 H.sub.5 88 CH     CH CH CH CH SO.sub.2 (CH.sub.2).sub.3 CHCH(CH.sub.2).sub.2 CH.sub.2     CH(CH.sub.3).sub.2 O C.sub.6     Footnotes To Table 1     .sup.(a) 1 H NMR (CDCl.sub.3) δ 8.75 (s,1H), 8.1-8.0 (m,2H), 7.9-7.     (m,2H), 6.5-6.4 (m,1H), 3.4-3.2 (m,6H), 1.9-1.2 (m,18H), 0.9-0.8 (m,3H).     .sup.(b) 1 H NMR (CDCl.sub.3) δ 8.75 (s,1H), 8.2 (s,1H), 4.2-3.9     (m,2H), 3.5-3.35 (m,2H), 3.3-3.1 (m,4H), 1.9-1.1 (m,23H), 0.9-0.8 (m,3H).     .sup.(c) 1 H NMR (CDCl.sub.3) δ 12.15 (bs,1H), 8.75 (s,1H), 8.1     (s,1H), 7.4-7.3 (m,2H), 7.2-7.0 (m,3H), 3.5-3.2 (m,7H), 1.95-1.2 (m,15H),     0.9-0.8 (m,3H).     .sup.(d) 1 H NMR (CDCl.sub.3) δ 12.0 (bs,1H), 8.8 (s,1H), 8.15     (s,1H), 7.4-7.05 (m,5H), 3.5-3.25 (m,6H), 1.95-1.45 (m,8H), 1.4-1.2     (m,8H), 0.85 (t,3H,J=6.6 Hz).

Utility

The compounds of the present invention are inhibitors of the enzymeacyl-CoA: cholesterol acyltransferase and are thus effective ininhibiting esterification and transport of cholesterol across theintestinal wall. In addition, the compounds are useful in preventing theformation of cholesterol ester rich macrophages (foam cells) in thearterial wall through the inhibition of cholesterol ester formation.Foam cells are a source of the large quantity of cholesterol ester foundin atheromatous lesions as opposed to the surrounding undiseased tissue.Thus inhibition of ACAT would decrease the accumulation and storage ofcholesterol esters in the arterial wall and prevent or inhibit theformation of atheromatous lesions.

A. Assay of the Inhibition of Acyl-CoA: Cholesterol Acyltransferase(ACAT) in Hepatic Microsomes

The ability of the compounds to inhibit ACAT, the enzyme responsible forthe intracellular synthesis of cholesteryl esters, was tested asfollows. Male Sprague Dawley rats weighing 150-300 g, were fed rat chowad libitum. The animals were fasted for eighteen hours prior to beingsacrificed by decapitation. The livers were perfused in situ with 50 mLof cold 0.25 M sucrose, excised, and homogenized in three volumes of0.1M phosphate buffer, pH 7.4, that contained 0.5 mM EDTA(ethylenediaminetetraacetic acid), 1.0 mM glutathione, 0.25 M sucroseand 20 μM leupeptin. Microsomes were obtained by differentialcentrifugation. The supernatant from an initial spin at 15,000 ×g for 15minutes was centrifuged at 105,000 ×g for 1 hour to pellet themicrosomes. The microsomes were suspended in 0.1M phosphate buffer with1 mM GSH, pH 7.4, reisolated by centrifugation, and stored at -70° C.

The control assay in a final volume of 200 μL consisted of 200 μg ofmicrosomal protein, 77 μM ¹⁴ C-oleoyl-CoA (10,000 dpm/nmol) in 0.1Mphosphate, pH 7.4, that contained 1 mM glutathione. Compounds were addedin 5 μL of DMSO (dimethyl sulfoxide) and additional controls were runwith DMSO only. All components, except the oleoyl-CoA, were preincubatedfor 15 min. at 37° C. prior to the initiation of the reaction by theaddition of oleoyl-CoA. The assay was terminated after 10 min by theaddition of 4 mL of chloroform:methanol (2:1::v:v). 30,000 dpm of ³H-cholesteryl oleate and 15 μg of unlabeled cholesteryl oleate and oleicacid were added as an internal standard and carriers, respectively.After allowing 20 min. for lipid extraction, 800 μL water was added toinduce phase separation. The chloroform layer was transferred to anothertube, dried under nitrogen and resuspended in 100 μL chloroform. Lipidswere separated by thin layer chromatography using ITLC-SA thin layerplates (Gelman Sciences) and a solvent system of hexane:diethylether:acetic acid (170:30:1::v:v:v). The lipids were visualized by theirinteraction with iodine vapor and the cholesteryl ester spot was cut outand placed into a scintillation vial and counted. The specific activityof ACAT in the control incubation averaged 260 pmol/min/mg microsomalprotein.

B. Assay of the Inhibition of Cholesterol Esterification in MammalianCells

The esterification of cholesterol was determined in the murinemacrophage-like cell line J774.A1. Cells were seeded in 35 mm wells at adensity of 300,000 cells per well in 2 mL of Dulbecco's Eagle Medium(DMEM) supplemented with 10% fetal bovine serum (FBS). Cells wereincubated at 37° C. in an atmosphere of 5% CO₂ and 93% humidity. After24 hours the media was changed to 0.68 mL 10% FBS-DMEM containing 34 μgof acetylated human low density lipoprotein (ac-LDL) to increase theintracellular concentration of cholesterol and promote esterification.At 41 hours, various inhibitors were added to the cells in DMSO (10μL/mL maximum). At 43 hours, the cells were pulsed with 0.1 mM ¹⁴C-oleic acid (10,000 dpm/nmol) complexed with BSA (bovine serum albumin)to follow cholesterol ester formation. The experiment was terminated at45 hours by washing the monolayers 3 times with 3 mL of Tris-bufferedsaline at 4° C. The lipids were extracted by incubating the monolayerswith 1.5 ml of hexane: isopropanol (3:2::v:v) for 30 min. under gentleagitation. During this period, 10,000 dpm ³ H-cholesteryl linoleate and10 μg of cholesteryl oleate were added as an internal standard andcarrier respectively. The organic solvent was removed and the cells werewashed with an additional 1.0 mL of hexane: isopropanol which wascombined with the original extract. The cells were allowed to dryovernight, digested with 1.5 mL of 0.2 N sodium hydroxide for 1 hour andan aliquot of the solubilized protein used for protein determinationusing the Lowry method. The organic extract was taken to dryness,resuspended in a solvent (3% diethyl ether, 97% hexane) for elution overa silica gel column and cholesterol esters extracted. Triglycerides wereeluted with a solution of 25% diethyl ether in hexane. Scintillationcocktail was added to the eluted samples to determine the amount ofradioactivity. The conversion of oleic acid to cholesteryl ester in thecontrol averaged 0.54 mmol/hour/mg protein and was increased upon theaddition of ac-LDL to about 10.69±0.69 mmol/hour/mg protein.

Using the assay methods described above, the compounds of this inventionare found to exhibit an activity of at least IC₅₀ <50 micromolar,thereby demonstrating and confirming the activity of these compounds aseffective antihypercholesterolemic and/or antiatherosclerotic agents.

Dosage Forms

The compounds of the present invention can be administered orally usingany pharmaceutically acceptable dosage form known in the art for suchadministration. The active ingredient can be supplied in solid dosageforms such as dry powders, granules, tablets or capsules, or in liquiddosage forms, such as syrups or aqueous suspensions. The activeingredient can be administered alone, but is generally administered witha pharmaceutical carrier. A valuable treatise with respect topharmaceutical dosage forms is Remington's Pharmaceutical Sciences, 16thEdition, 1980.

In their therapeutic use as antihypercholesterolemic and/orantiatherosclerotic agents, the compounds of the invention areadministered to the patient at dosage levels of 1 to 28 g per day. For anormal male adult human of approximately 70 kg of body weight, thistranslates into a dosage of 14 to 400 mg per kilogram body weight perday. The dosage administered will, of course, vary depending upon knownfactors such as the age, health, and weight of the recipient, nature andextent of symptoms, kind of concurrent treatment, frequency oftreatment, and the effect desired. Useful pharmaceutical dosage formsfor administration of the compounds of this invention can be illustratedas follows:

Tablets

Tablets are prepared by conventional procedures so that the dosage unitis 500 milligrams of active ingredient, 150 milligrams of lactose, 50milligrams of cellulose and 10 milligrams of magnesium stearate.

Capsules

Capsules are prepared by conventional procedures so that the dosage unitis 500 milligrams of active ingredient, 100 milligrams of cellulose and10 milligrams of magnesium stearate.

    ______________________________________                                        Syrup                                                                                         Wt. %                                                         ______________________________________                                        Active Ingredient 10                                                          Liquid Sugar      50                                                          Sorbitol          20                                                          Glycerine          5                                                          Flavor, Colorant and                                                                            as required                                                 Preservative                                                                  Water             as required                                                 ______________________________________                                    

The final volume is brought up to 100% by the addition of distilledwater.

    ______________________________________                                        Aqueous Suspension                                                                             Wt. %                                                        ______________________________________                                        Active Ingredient  10                                                         Sodium Saccharin   0.01                                                       Keltrol ® (Food Grade                                                                        0.2                                                        Xanthan Gum)                                                                  Liquid Sugar       5                                                          Flavor, Colorant and                                                                             as required                                                Preservative                                                                  Water              as required                                                ______________________________________                                    

Xanthan gum is slowly added into distilled water before adding theactive ingredient and the rest of the formulation ingredients. The finalsuspension is passed through a homogenizer to assure the elegance of thefinal products.

    ______________________________________                                        Resuspendable Powder                                                                              Wt. %                                                     ______________________________________                                        Active Ingredient     50.0                                                    Lactose               35.0                                                    Sugar                 10.0                                                    Acacia                4.7                                                     Sodium Carboxylmethylcellulose                                                                      0.3                                                     ______________________________________                                    

Each ingredient is finely pulverized and then uniformly mixed together.Alternatively, the powder can be prepared as a suspension and then spraydried.

    ______________________________________                                        Semi-Solid Gel                                                                                Wt. %                                                         ______________________________________                                        Active Ingredient 10                                                          Sodium Saccharin  0.02                                                        Gelatin           2                                                           Colorant, Flavor and                                                                            as required                                                 Preservative                                                                  Water             as required                                                 ______________________________________                                    

Gelatin is prepared in hot water. The finely pulverized activeingredient is suspended in the gelatin solution and then the rest of theingredients are mixed in. The suspension is filled into a suitablepackaging container and cooled down to form the gel.

    ______________________________________                                        Semi-Solid Paste                                                                                Wt. %                                                       ______________________________________                                        Active Ingredient   10                                                        Gelcarin ® (Carrageenin gum)                                                                  1                                                         Sodium Saccharin    0.01                                                      Colorant, Flavor and                                                                              as required                                               Preservative                                                                  Water               as required                                               ______________________________________                                    

Gelcarin® is dissolved in hot water (around 80° C.) and then thefine-powder active ingredient is suspended in this solution. Sodiumsaccharin and the rest of the formulation ingredients are added to thesuspension while it is still warm. The suspension is homogenized andthen filled into suitable containers.

    ______________________________________                                        Emulsifiable Paste                                                                              Wt. %                                                       ______________________________________                                        Active Ingredient   30                                                        Tween ® 80 and Span ® 80                                                                  6                                                         Keltrol ®       0.5                                                       Mineral Oil         63.5                                                      ______________________________________                                    

All the ingredients are carefully mixed together to make a homogeneouspaste.

The term "consisting essentially of" in the present disclosure isintended to have its customary meaning, namely, that all specifiedmaterials and conditions are very important in practicing the inventionbut that unspecified materials and conditions are not excluded so longas they do not prevent the benefits of the invention from beingrealized.

The foregoing disclosure includes all the information deemed essentialto enable those of skill in the art to practice the claimed invention.Because the cited publications and applications may provide furtheruseful information, however, these cited materials are herebyincorporated by reference.

What is claimed is:
 1. A compound of the formula (I): ##STR54## wherein:X is S(O)_(r), O, NR⁴ or CH₂ ;J is C₂ -C₁₀ alkylene, C₃ -C₁₀ alkenyleneor C₃ -C₁₀ alkynylene; Y is O, S, or NH; Z is NHR³, OR³ or R³ ; R¹ isselected independently from H, NO₂, Br, Cl, F, CF₃, CN, CH₃ S(O)_(r), C₁-C₈ alkyl or alkoxy, C₁ -C₄ carboalkoxy, NR₅ R₆ or NR₅ COR₆ ; R² is C₁-C₈ alkyl, C₃ -C₇ cycloalkyl, C₃ -C₈ alkenyl or alkynyl, C₇ -C₁₄araalkyl where the aryl group is optionally substituted with 1 to 3groups selected from C₁ -C₄ alkyl or alkoxy, F, Br, Cl, OH, CN, CO₂ H,CF₃, C₁ -C₄ carboalkoxy, NR⁵ R⁶, or NR⁵ COR⁶ ; phenyl optionallysubstituted with 1 to 3 groups selected from C₁ -C₄ alkyl or alkoxy, F,Br, Cl, OH, CN, CO₂ H, CF₃, C₁ -C₄ carboalkoxy, NR⁵ R⁶ or NR⁵ COR⁶ ;benzyl optionally substituted with 1 to 3 groups selected from C₁ -C₄alkyl or alkoxy, F, Br, Cl, OH, CN, CO₂ H, CF₃, C₁ -C₄ carboalkoxy, NR⁵R⁶, or NR⁵ COR⁶ ; 2-, 3-, or 4- pyridinyl, pyrimidinyl; or biphenyl; R³is C₃ -C₇ cycloalkyl, C₄ -C₁₀ cycloalkylalkyl, C₃ -C₆ alkenyl oralkynyl, C₁ -C₃ perfluoroalkyl, C₇ -C₁₄ araalkyl where the aryl group isoptionally substituted with 1 to 3 groups selected from C₁ -C₄ alkyl oralkoxy, F, Br, Cl, OH, CN, CO₂ H, CF₃, C₁ -C₄ carboalkoxy, NR⁵ R⁶, orNR⁵ COR⁶ ; phenyl optionally substituted with 1 to 3 groups selectedfrom C₁ -C₄ alkyl or alkoxy, C₃ -C₈ branched alkyl, F, Br, Cl, OH, CN,CO₂ H, CF₃, C₁ -C₄ carboalkoxy, NR⁵ R⁶, or NR⁵ COR⁶ ; benzyl optionallysubstituted with 1 to 3 groups selected from C₁ -C₄ alkyl or alkoxy, F,Br, Cl, OH, CN, CO₂ H, CF₃, C₁ -C₄ carboalkoxy, NR.sup. 5 R⁶, or NR⁵COR⁶ ; 2-, 3-, or 4- pyridinyl, pyrimidinyl; or biphenyl; R⁴ is H, C₁-C₆ alkyl or benzyl; R⁵ and R⁶ are selected independently from H or C₁-C₄ alkyl; r is 0 to 2; or a pharmaceutically acceptable salt thereof.2. A compound of claim 1 wherein:X is S(O)_(r) ; J is C₂ -C₁₀ alkyleneor C₄ -C₉ branched alkylene; Y is O; Z is NHR₃ ; R¹ is selectedindependently from H, NO₂, C₁ -C₈ alkyl or alkoxy, C₃ -C₈ branchedalkyl, C₁ -C₄ carboalkoxy, NR⁵ R⁶ or NR⁵ COR⁶ ; R² is C₁ -C₈ alkyl, C₃-C₇ cycloalkyl, C₇ -C₁₄ araalkyl where the aryl group is optionallysubstituted with 1 to 3 groups selected from CH₃, CH₃ O, F, Br, Cl, OH,CN, CO₂ H, CF₃, NH₂, NO₂, or di(C₁ -C₄) alkylamino; phenyl optionallysubstituted with 1 to 3 groups selected from CH₃, CH₃ O, F, Br, Cl, OH,CN, CO₂ H, CF₃, NH₂, NO₂, or di(C₁ -C₄)alkylamino; benzyl optionallysubstituted with 1 to 3 groups selected from CH₃, CH₃ O, F, Br, Cl, OH,CN, CO₂ H, CF₃, NH₂, NO₂, or di(C₁ -C₄)alkylamino; 2-, 3-, or4-pyridinyl, pyrimidinyl; or biphenyl; R⁴ is H.
 3. A compound of claim 1wherein:X is S; J is C₂ -C₁₀ alkylene; R¹ is selected from H, CH₃ or NO₂; R² is C₁ -C₈ alkyl, C₇ -C₁₄ araalkyl where the aryl group isoptionally substituted with 1 to 3 groups selected from CH₃, CH₃ O, F,NH₂, NO₂, or di(C₁ -C₄) alkylamino; phenyl optionally substituted with 1to 3 groups selected from CH₃, CH₃ O, F, NH₂, NO₂, or di(C₁ -C₄)alkylamino; benzyl optionally substituted with 1 to 3 groups selectedfrom CH₃, CH₃ O, F, NH₂, NO₂, or di(C₁ -C₄) alkylamino; 2-, 3-, or 4-pyridinyl, pyrimidinyl; or biphenyl; R³ is C₁ -C₈ alkyl, C₇ -C₁₄araalkyl where the aryl group is optionally substituted with 1 to 3groups selected from C₁ -C₄ alkyl or alkoxy, F, NH₂, NO₂, C₁ -C₄carboalkoxy, or di(C₁ -C₄)alkylamino; phenyl optionally substituted with1 to 3 groups selected from C₁ -C₄ alkyl or alkoxy, F, NH₂, NO₂, C₁ -C₄carboalkoxy, or di(C₁ -C₄)alkylamino; benzyl optionally substituted with1 to 3 groups selected from C₁ -C₄ alkyl or alkoxy, F, NH₂, NO₂, C₁ -C₄carboalkoxy, or di(C₁ -C₄) alkylamino; 2-, 3-, or 4- pyridinyl,pyrimidinyl; or biphenyl.
 4. The compound which isN'-(2,4-Difluorophenyl)-N-heptyl-N-[5-(1H-pyrazolo(3,4-d)pyrimidin-4-ylthio)pentyl]urea.5. A method of treating hypercholesterolemia or atherosclerosis in amammal comprising administering to the mammal a therapeuticallyeffective amount of a compound of claim
 4. 6. A pharmaceuticalcomposition comprising an effective ACAT inhibiting amount orantihypercholesterolemic amount or antiatherosclerotic amount of acompound of claim 1 and a pharmaceutically acceptable carrier.
 7. Apharmaceutical composition comprising an effective ACAT inhibitingamount or antihypercholesterolemic amount or antiatherosclerotic amountof a compound of claim 2 and a pharmaceutically acceptable carrier.
 8. Apharmaceutical composition comprising an effective ACAT inhibitingamount or antihypercholesterolemic amount or antiatherosclerotic amountof a compound of claim 3 and a pharmaceutically acceptable carrier.
 9. Amethod of treating hypercholesterolemia or atherosclerosis in a mammalcomprising administering to the mammal a therapeutically effectiveamount of a compound of claim
 3. 10. A pharmaceutical compositioncomprising an effective ACAT inhibiting amount orantihypercholesterolemic amount or antiatherosclerotic amount of acompound of claim 4 and a pharmaceutically acceptable carrier.
 11. Amethod of treating hypercholesterolemia or atherosclerosis in a mammalcomprising administering to the mammal a therapeutically effectiveamount of a compound of claim
 1. 12. A method of treatinghypercholesterolemia or atherosclerosis in a mammal comprisingadministering to the mammal a therapeutically effective amount of acompound of claim 2.